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<p>Natural products from <i>Bulbophyllum</i> species were systematically investigated as potential antioxidant scaffolds using density functional theory, real-space topological analyses, pharmacokinetic and toxicity prediction, molecular docking, and 100 ns molecular dynamics simulations, in comparison with Quercetin and Resveratrol. Frontier molecular orbital analysis revealed relatively large HOMO–LUMO gaps for the derivatives (5.41–5.67&#xa0;eV) compared to 3.97&#xa0;eV for the reference compounds, indicating higher electronic stability. Muscatilin displayed the lowest hardness (2.70&#xa0;eV) and highest softness (0.185 eV<sup>−1</sup>), suggesting enhanced chemical reactivity. Real-space topological analyses (QTAIM, RDG/NCI, IRI, DORI, LOL, ELF) provide a molecular-level interpretation of interactions relevant to antioxidant behavior. In particular, Muscatilin exhibited a more favorable electron density distribution that may facilitate radical stabilization following hydrogen or electron transfer, thereby suggesting improved antioxidant potential. SwissADME profiling predicted favorable drug-likeness, high gastrointestinal absorption, and blood-brain barrier permeability for all compounds except Quercetin, while toxicity prediction showed high LD<sub>50</sub> values for Tristin, Muscatilin, and Gigantol (2260&#xa0;mg/kg) with nephrotoxicity as a shared class and improved cardiac safety for Muscatilin and Gigantol. Molecular docking results suggested binding affinities ranging from − 7.2 to − 9.2&#xa0;kcal/mol toward bovine superoxide dismutase (SOD), with Muscatilin showing the most favorable interaction. Molecular dynamics simulations further indicated stable ligand binding within the SOD active channel, supported by MM-GBSA binding energy estimates. Collectively, Muscatilin and Gigantol are predicted to exhibit promising activity-safety profiles and may serve as potential antioxidant lead compounds, warranting further experimental validation.</p>

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Theoretical visualization of covalent and non-covalent interactions: molecular diversity and substituent effects governing the reactivity of Bulbophyllum bibenzyl derivatives

  • 期刊论文

  • 发表日期：

    2026年5月29日

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  • Fatiha Guenfoud,
  • Oussama Khaoua,
  • Noura Benbellat

摘要

Natural products from Bulbophyllum species were systematically investigated as potential antioxidant scaffolds using density functional theory, real-space topological analyses, pharmacokinetic and toxicity prediction, molecular docking, and 100 ns molecular dynamics simulations, in comparison with Quercetin and Resveratrol. Frontier molecular orbital analysis revealed relatively large HOMO–LUMO gaps for the derivatives (5.41–5.67 eV) compared to 3.97 eV for the reference compounds, indicating higher electronic stability. Muscatilin displayed the lowest hardness (2.70 eV) and highest softness (0.185 eV−1), suggesting enhanced chemical reactivity. Real-space topological analyses (QTAIM, RDG/NCI, IRI, DORI, LOL, ELF) provide a molecular-level interpretation of interactions relevant to antioxidant behavior. In particular, Muscatilin exhibited a more favorable electron density distribution that may facilitate radical stabilization following hydrogen or electron transfer, thereby suggesting improved antioxidant potential. SwissADME profiling predicted favorable drug-likeness, high gastrointestinal absorption, and blood-brain barrier permeability for all compounds except Quercetin, while toxicity prediction showed high LD50 values for Tristin, Muscatilin, and Gigantol (2260 mg/kg) with nephrotoxicity as a shared class and improved cardiac safety for Muscatilin and Gigantol. Molecular docking results suggested binding affinities ranging from − 7.2 to − 9.2 kcal/mol toward bovine superoxide dismutase (SOD), with Muscatilin showing the most favorable interaction. Molecular dynamics simulations further indicated stable ligand binding within the SOD active channel, supported by MM-GBSA binding energy estimates. Collectively, Muscatilin and Gigantol are predicted to exhibit promising activity-safety profiles and may serve as potential antioxidant lead compounds, warranting further experimental validation.